Central Nervous System (NS) disorders are diseases of any component of the brain and the spinal cord. NS disorders include disorders in which the nervous system is affected during the entire progression of the diseases such as neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis (ALS), degenerative ataxias such as Friedrich's ataxia, multiple sclerosis, multiple system atrophy and leukodystrophies), cerebrovascular diseases (e.g., global or local ischemia, intracerebral haemorrhage, stroke), seizures and epilepsy, viral diseases (e.g., meningitis, encephalitis), brain tumors and neuroinflammatory diseases. NS disorders also include disorders in which the nervous system is only affected during the latest stages of the development of the disorder. These disorders comprise rare metabolic diseases such as organic acidemias or fatty acid disorders and genetic mitochondrial disorders.
Neurodegenerative diseases are characterised by the progressive loss of structure or function of neurons, including death of neurons. These conditions are progressive and often fatal. The process of neurodegeneration is not well understood and the diseases that stem from it have, as yet, no cures in spite of treatments being constantly sought.
Some neurodegenerative diseases also include an inflammatory component such as multiple sclerosis which traditionally was considered as inflammatory mediated demyelinating diseases but, in fact, is a neurodegenerative disease in which axonal damage, neuronal death and atrophy of the central NS are the principal causes of irreversible neurological disability in patients. Thus, multiple sclerosis can be considered as a neurodegenerative disease but also as a neuroinflammatory disease or autoimmune disease.
Leukodystrophies are a group of generic NS disorders whose main feature is the degeneration of the white matter in the brain. One disorder of this group is adrenoleukodystrophy (X-linked adrenoleukodystrophy or X-ALD). This is a rare, inherited disorder that leads to progressive damage to the brain and other tissues and eventually death. This disease can be considered both as neurodegenerative and neuroinflammatory.
X-ALD presents three main phenotypes: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords. (ii) cerebral adrenomyeloneuropathy with brain demyelination (cAMN), and (iii) childhood variant (cALD) characterized by severe cerebral demyelination. X-ALD is the most frequently inherited leukodystrophy, with a minimum incidence of 1 in 17,000 including hemizygous males and carrier females.
Cerebrovascular diseases are a group of brain dysfunctions related to disease of the blood vessels supplying the brain. There are four types: stroke, transient ischaemic attack (TIA), subarachnoid haemorrhage and vascular dementia.
Epilepsy is an unpredictable, serious and potentially fatal disorder of the nervous system. About 50 million people worldwide have epilepsy.
Brain tumours are generated by an abnormal and uncontrolled cell division not only in the brain (neurons or glial cells) but also in blood vessels, cranial nerves, meninges, skull, and pituitary or pineal glands. Brain tumours also include those that have spread from primary cancer cells located in other organs (metastasis).
Nervous system viral diseases are caused by viral infections in the NS. These infections can induce neurological dysfunction and potentially serious inflammatory diseases such as encephalitis, an inflammation of the brain itself, meningitis that results in inflammation of the meninges or myelitis that means spinal cord inflammation. Rabies, measles, mumps, poliomyelitis, herpes simplex or varicella-zoster are types of nervous system viral infections.
Rare metabolic diseases (also known as Inborn Errors of Metabolism) are usually monogenic diseases where certain metabolic pathways are perturbed thus originating dysfunctions, in many cases on the central NS. They are chronically debilitating and life-threatening conditions.
Genetic mitochondrial diseases can be caused by mutations in either mtDNA or nDNA, that impair mitochondrial function and typically result in very severe multisystem disease from birth, including severe manifestations on the NS.
There is an urgent need for new treatments of central NS disorders.
A wide variety of deuterium enriched 2,4-thiazolidinediones have been described in US 2014/0275180. This document also discloses their prophetic use in the treatment of a variety of different diseases. However, this document fails to provide any evidence in this regard or regarding the ability of these compounds to cross the blood-brain barrier (BBB).
Pioglitazone is a drug marketed for use in the treatment of diabetes mellitus type 2. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ) and it has been proposed for the treatment of some neurodegenerative diseases including Alzheimer's, Parkinson's disease, ALS and Friedreich's ataxia. US2013/0274295 discloses the utility of Pioglitazone in the treatment of X-ALD based on pre-clinical data. Although pre-clinical models have shown promising results, clinical trials to date have failed to show clinical benefits in any of these extremely serious conditions.
In addition, Pioglitazone has been associated with unwanted side effects including cardiovascular effects, fluid retention, weight gain and bladder cancer. High doses of Pioglitazone are therefore undesirable as high systemic exposure would be likely to result in serious side effects.
Pioglitazone is a “dirty” drug which is converted to many metabolites in vivo. The metabolic pathway of Pioglitazone after oral administration has been studied in several animal species and in humans and the metabolites have been described in the literature (see e.g. Sohda et al, Chem. Pharm. Bull., 1995, 43(12), 2168-2172) and Maeshiba et al, Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). At least six metabolites have been identified, named M-I to M-VI. Amongst these metabolites, M-II, M-III and M-IV show some pharmacological activity but are less active than Pioglitazone in diabetic preclinical models.
The distribution of Pioglitazone and its metabolites in various tissues after oral administration of [14C]-Pioglitazone to rats has also been studied (Maeshiba et al, Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). In most tissues the concentrations of Pioglitazone and metabolites M-I to M-VI were lower than that in plasma and one of the lowest concentrations of radioactivity was found in the brain where only Pioglitazone was mainly detected.